The objectives are four: 1) to explain unexpected oscillations in plasma glucose and insulin levels occurring during prolonged infusions of glucose, 2) to express understanding of these oscillations through a new computer simulation based upon our present model of glucose regulation, 3) to extend our present model by adding neural control influences on the pancreas and liver, and 4) to validate the new model by five experimental studies. Study no.1 involves autoperfusion of the canine gracilis muscle, Flow rate and arterial-venous concentration difference for glucose will be measured at multiple plucose input concentrations. Insulin signals for various forms will be presented, and the threshhold, delay and dynamics of the "on" and "off" responses to insuling will be defined. Study no. 2 will explore central neural control of the pancreas (insulin and glucagon secretion) by the hyplthalamus. Test materials will be presented into the third ventricle, including glucose and insulin in small doses, and the effects of these central signals on the oscillations induced by simultaneous loading with systemic glucose infusions will be determined. Effects of peripheral autonomic effector blockade on the oscillations will also be studied. Study no. 3 will determine whether periodic variations in glucaos production contributes to the oscillations generated during glucose infusions. Osotope rate dilution (U-C14 glucose) will be employed to estimate production rates. Study no. 4 will determine the phase relationships among oscillations in total plasma insulin and glucose levels, and the extraction of glucose by the large skeletal muscle bed of the hind limbs. Study no. 5 will determine the effect of mild and severe damage of pancreatic beta cells on the oscillations generated by glucose infusions. As data from each study becomes available, a computer simulation will be updated. We hope to conclude with a model capable of diagnosing prediabetes, when programmed with glucose infusion data from patients whose metabolic status is unclear after conventional clinical tests.